PPARγ agonism attenuates cocaine seeking behavior via association with ERK MAPK

The nucleus accumbens integrates information from a number of cortical and limbic structures such as the prefrontal cortex and hippocampus and alterations of this neurocircuitry during drug taking and abstinence is thought to underlie relapse behaviors. ERK, a protein vital for learning and memory, is altered by cocaine use and abstinence. Our lab demonstrated PPARγ agonism rescued cognitive impairment in an animal model of Alzheimer’s disease and that this rescue involved ERK. Given the role of altered learning and memory circuitry in addiction, and our recent evidence that PPARγ is involved in restoring hippocampal cognitive deficits through ERK, the current study tested the hypothesis that the prevention of drug-induced alterations of ERK in brain regions critical for the integration of drug cues and context, which lead to increased cocaine seeking, could be attenuated by targeting PPARγ. We found PPARγ agonism attenuated cocaine cue reactivity in Sprague Dawley rats while administration of a selective PPARγ antagonist, GW 9662, reversed the behavioral effects of PPARγ agonism. We determined PPARγ agonism rescued dysregulated ERK activity in the medial prefrontal cortex, hippocampus, amygdala, and nucleus accumbens and GW 9662 prevented this rescue in the medial prefrontal cortex and hippocampus. PPARy agonism during forced abstinence prevented a decrease in a nuclear pERK/PPARγ protein complex after a cocaine cue reactivity test in the hippocampus and medial prefrontal cortex demonstrating a direct molecular mechanism for PPARy agonism action on pERK dependent plasticity. Our results demonstrate that PPARγ agonism attenuated cocaine seeking through a pERK dependent mechanism which prevented dysregulation of basic reward and memory circuitry that is known to become altered with drug taking, abstinence, and cue reactivity.

Name thesis:degree_name

Neuroscience (Doctoral)

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Addiction

Grantor

The University of Texas Medical Branch at Galveston

Author dc:creator

• Miller, William Ryan

Advisor dc:contributor.advisor

• Dineley, Kelly T

Committee members dc:contributor.committeemember

• Cunningham, Kathryn
• Green, Thomas
• Hommel, Jonathan
• McGinty, Jacqueline

• PPARy, pERK, Cocaine

Handle dc:identifier.uri

http://hdl.handle.net/2152.3/719

OAI identifier oai:identifier

oai:utmb-ir.tdl.org:2152.3/719